Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice
- PMID: 32366484
- DOI: 10.1183/13993003.00404-2020
Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice
Abstract
It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.
Copyright ©ERS 2020.
Conflict of interest statement
Conflict of interest: Jie-Sen Zhou has nothing to disclose. Conflict of interest: Zhou-Yang Li has nothing to disclose. Conflict of interest: Xu-Chen Xu has nothing to disclose. Conflict of interest: Yun Zhao has nothing to disclose. Conflict of interest: Yong Wang has nothing to disclose. Conflict of interest: Hai-Pin Chen has nothing to disclose. Conflict of interest: Min Zhang has nothing to disclose. Conflict of interest: Yin-Fang Wu has nothing to disclose. Conflict of interest: Tian-Wen Lai has nothing to disclose. Conflict of interest: Chun-Hong Di has nothing to disclose. Conflict of interest: Ling-Ling Dong has nothing to disclose. Conflict of interest: Juan Liu has nothing to disclose. Conflict of interest: Nan-Xia Xuan has nothing to disclose. Conflict of interest: Chen Zhu has nothing to disclose. Conflict of interest: Yan-Ping Wu has nothing to disclose. Conflict of interest: Hua-Qiong Huang has nothing to disclose. Conflict of interest: Fu-Gui Yan has nothing to disclose. Conflict of interest: Wen Hua has nothing to disclose. Conflict of interest: Yi Wang has nothing to disclose. Conflict of interest: Wei-Ning Xiong has nothing to disclose. Conflict of interest: Hui Qiu has nothing to disclose. Conflict of interest: Tao Chen has nothing to disclose. Conflict of interest: Dong Weng has nothing to disclose. Conflict of interest: Hui-Ping Li has nothing to disclose. Conflict of interest: Xiaobo Zhou has nothing to disclose. Conflict of interest: Lie Wang has nothing to disclose. Conflict of interest: Fang Liu has nothing to disclose. Conflict of interest: Xin Lin has nothing to disclose. Conflict of interest: Song-Min Ying has nothing to disclose. Conflict of interest: Wen Li has nothing to disclose. Conflict of interest: Mitsuru Imamura has nothing to disclose. Conflict of interest: M.E. Choi has nothing to disclose. Conflict of interest: M.R. Stampfli has nothing to disclose. Conflict of interest: A.M.K. Choi has nothing to disclose. Conflict of interest: Zhi-Hua Chen has nothing to disclose. Conflict of interest: Hua-Hao Shen has nothing to disclose.
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